Hemolytic Dynamics of Weekly Primaquine Antirelapse Therapy Among Cambodians With Acute Plasmodium vivax Malaria With or Without Glucose-6-Phosphate Dehydrogenase Deficiency.

BACKGROUND: Hemoglobin (Hb) data are limited in Southeast Asian glucose-6-phosphate dehydrogenase (G6PD) deficient (G6PD-) patients treated weekly with the World Health Organization-recommended primaquine regimen (ie, 0.75 mg/kg/week for 8 weeks [PQ 0.75]). METHODS: We treated Cambodians who had acute Plasmodium vivax infection with PQ0.75 and a 3-day course of dihydroartemisinin/piperaquine and determined the Hb level, reticulocyte count, G6PD genotype, and Hb type. RESULTS: Seventy-five patients (male sex, 63) aged 5-63 years (median, 24 years) were enrolled. Eighteen were G6PD deficient (including 17 with G6PD Viangchan) and 57 were not G6PD deficient; 26 had HbE (of whom 25 were heterozygous), and 6 had α-/ß-thalassemia. Mean Hb concentrations at baseline (ie, day 0) were similar between G6PD deficient and G6PD normal patients (12.9 g/dL [range, 9‒16.3 g/dL] and 13.26 g/dL [range, 9.6‒16 g/dL], respectively; P = .46). G6PD deficiency (P = <.001), higher Hb concentration at baseline (P = <.001), higher parasitemia level at baseline (P = .02), and thalassemia (P = .027) influenced the initial decrease in Hb level, calculated as the nadir level minus the baseline level (range, -5.8-0 g/dL; mean, -1.88 g/dL). By day 14, the mean difference from the day 7 level (calculated as the day 14 level minus the day 7 level) was 0.03 g/dL (range, -0.25‒0.32 g/dL). Reticulocyte counts decreased from days 1 to 3, peaking on day 7 (in the G6PD normal group) and day 14 (in the G6PD deficient group); reticulocytemia at baseline (P = .001), G6PD deficiency (P = <.001), and female sex (P = .034) correlated with higher counts. One symptomatic, G6PD-deficient, anemic male patient was transfused on day 4. CONCLUSIONS: The first PQ0.75 exposure was associated with the greatest decrease in Hb level and 1 blood transfusion, followed by clinically insignificant decreases in Hb levels. PQ0.75 requires monitoring during the week after treatment. Safer antirelapse regimens are needed in Southeast Asia. CLINICAL TRIALS REGISTRATION: ACTRN12613000003774.

Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency.

BACKGROUND: Primaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd. METHODS: From January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants' G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] <7 g/dL), (2) a >25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %. RESULTS: We enrolled 75 patients with a median age of 24 years (range 5-63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6-16) and G6PDn (13.5 g/dL, range 9-16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2-15.3) versus 12.4 g/dL (8.8-15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0-D5 Hb, 10.0-7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury. CONCLUSIONS: Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored. TRIAL REGISTRATION: The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774.

Evaluation of community-based systems for the surveillance of day three-positive Plasmodium falciparum cases in Western Cambodia.

BACKGROUND: Delayed clearance of Plasmodium falciparum parasites is used as an operational indicator of potential artemisinin resistance. Effective community-based systems to detect P. falciparum cases remaining positive 72 hours after initiating treatment would be valuable for guiding case follow-up in areas of known resistance risk and for detecting areas of emerging resistance. METHODS: Systems incorporating existing networks of village malaria workers (VMWs) to monitor day three-positive P. falciparum cases were piloted in three provinces in western Cambodia. Quantitative and qualitative data were used to evaluate the wider feasibility and sustainability of community-based surveillance of day three-positive P. falciparum cases. RESULTS: Of 294 day-3 blood slides obtained across all sites (from 297 day-0 positives), 63 were positive for P. falciparum, an overall day-3 positivity rate of 21%. There were significant variations in the systems implemented by different partners. Full engagement of VMWs and health centre staff is critical. VMWs are responsible for a range of individual tasks including preparing blood slides on day-0, completing forms, administering directly observed therapy (DOT) on days 0-2, obtaining follow-up slides on day-3 and transporting slides and paperwork to their supervising health centre. When suitably motivated, unsalaried VMWs are willing and able to produce good quality blood smears and achieve very high rates of DOT and day-3 follow-up. CONCLUSIONS: Community-based surveillance of day-3 P. falciparum cases is feasible, but highly intensive, and as such needs strong and continuous support, particularly supervision and training. The purpose and role of community-based day-3 surveillance should be assessed in the light of resource requirements; scaling-up would need to be systematic and targeted, based on clearly defined epidemiological criteria. To be truly comprehensive, the system would need to be extended beyond VMWs to other public and private health providers.

Studies needed to address public health challenges of the 2009 H1N1 influenza pandemic: insights from modeling.

In light of the 2009 influenza pandemic and potential future pandemics, Maria Van Kerkhove and colleagues anticipate six public health challenges and the data needed to support sound public health decision making.

Epidemic malaria in the highlands of Papua New Guinea.

As part of a larger study into the epidemiology of malaria in the highlands of Papua New Guinea, outbreak investigations were carried out at the end of the 2002 rainy season in 11 villages situated between 1,400 and 1,700 meters above sea level that had reported epidemics. Locations and timing of these epidemics corresponded largely to those reported in the pre-control era of the 1960s and 1970s. On average, 28.8% (range = 10.3-63.2%) of people in each of the 11 villages were found to be infected with malaria. Plasmodium falciparum accounted for 59% of all identified infections and P. vivax for 34%. The majority (53%) of infections were symptomatic. Although symptomatic infections were most common in children 2-9 years of age (36%), even in adults a prevalence of 20% was observed. A comparison with earlier non-epidemic data in three of the villages without easy access to health care showed markedly increased levels of morbidity, with 6-10-fold increases in parasite prevalence, a 3-fold increase in both measured and reported fevers, and a 12-fold increase in enlarged spleens. The average hemoglobin levels were reduced by 2.3-3.5 g/dL, with a concurrent increase in moderate to severe anemia (hemoglobin level < 7.5 g/dL) from 0.0-3.3% to 3.8-18.4%. These massive increases in morbidity have devastating impact on the affected communities and highlight that malaria epidemics are a serious and increasing public health problem in the highlands of Papua New Guinea.

The epidemiology of malaria in the Papua New Guinea highlands: 1. Western Highlands Province.

Despite a resurgence of malaria in many Papua New Guinea highlands and highlands fringe areas after the cessation of control activities in the early 1980s the malaria situation in these areas has received little attention. A series of cross-sectional surveys were therefore carried out to provide accurate and up-to-date information on the prevalence of malaria and the risk of epidemics and to propose adequate malaria control strategies. Studies in 24 villages in Western Highlands Province found the prevalence of malarial infections to be strongly correlated with altitude, ranging from 1.6% at altitudes of 1500-1800 m to over 30% in villages below 900 m. Malaria outbreaks were observed at the end of the rainy season. All four human malaria species were present with P. falciparum infections clearly dominating. The relative importance of P. vivax increased with altitude, while both P. malariae and P. ovale were rare. Many infections were of low density. While malaria is an important source of febrile illness in endemic areas below 1500 m altitude, only few observed or reported fevers are due to malarial infections in higher, nonendemic areas. Rates of enlarged spleens, mean haemoglobin levels and the prevalence of anaemia (Hb <7.5 g/dl) were strongly linked to the level of malaria found in each community and were associated with both altitude and concurrent malarial infection. Based on the survey results, areas of different malaria epidemiology are delineated and options for control in each area are discussed.

Focused Screening and Treatment (FSAT): a PCR-based strategy to detect malaria parasite carriers and contain drug resistant P. falciparum, Pailin, Cambodia.

Recent studies have shown that Plasmodium falciparum malaria parasites in Pailin province, along the border between Thailand and Cambodia, have become resistant to artemisinin derivatives. To better define the epidemiology of P. falciparum populations and to assess the risk of the possible spread of these parasites outside Pailin, a new epidemiological tool named "Focused Screening and Treatment" (FSAT), based on active molecular detection of asymptomatic parasite carriers was introduced in 2010. Cross-sectional malariometric surveys using PCR were carried out in 20 out of 109 villages in Pailin province. Individuals detected as P. falciparum carriers were treated with atovaquone-proguanil combination plus a single dose of primaquine if the patient was non-G6PD deficient. Interviews were conducted to elicit history of cross-border travel that might contribute to the spread of artemisinin-resistant parasites. After directly observed treatment, patients were followed up and re-examined on day 7 and day 28. Among 6931 individuals screened, prevalence of P. falciparum carriers was less than 1%, of whom 96% were asymptomatic. Only 1.6% of the individuals had a travel history or plans to go outside Cambodia, with none of those tested being positive for P. falciparum. Retrospective analysis, using 2010 routine surveillance data, showed significant differences in the prevalence of asymptomatic carriers discovered by FSAT between villages classified as "high risk" and "low risk" based on malaria incidence data. All positive individuals treated and followed-up until day 28 were cured. No mutant-type allele related to atovaquone resistance was found. FSAT is a potentially useful tool to detect, treat and track clusters of asymptomatic carriers of P. falciparum along with providing valuable epidemiological information regarding cross-border movements of potential malaria parasite carriers and parasite gene flow.